How Fosmidomycin Affects Malaria

Fosmidomycin was isolated in the 1970's by Fujisawa Pharmaceuticals (Osaka, Japan) as a naturally occurring antibiotic produced by Streptomyces lavendulae. Without knowledge of its molecular target, fosmidomycin was investigated in Phase II studies as a potential treatment for urinary tract infections and while proving effective for acute uncomplicated infections, it was less effective for the treatment of complicated infections, and further development was halted.

Fosmidomycin acts through inhibition of isoprenoid biosynthesis. In all organisms, isoprenoids are synthesised from isopentenyl pyrophosphate (IPP) as a common precursor molecule. In animal and human cells, IPP is produced via the well-known mevalonate pathway. In contrast, many eubacteria and all plant cells synthesise IPP by the DOXP pathway (also depicted MEP pathway or non-mevalonate pathway). The discovery, that plasmodia, the malaria parasites, rely on the non-mevalonate pathway as the one and only means of synthesising IPP, brought up the idea of testing fosmidomycin as an antimalaeial agent.

The enzymes of the DOXP pathway inside the plastid-like organelle of malaria parasites (apicoplast) were identified as a selective target for anti-malaria chemotherapy. Fosmidomycin acts as an inhibitor of DOXP reductoisomerase, the second enzyme in the reaction cascade of the DOXP pathway.

The interaction of fosmidomycin with most current anti-malaria drugs and antibiotics was investigated in a series of in vitro experiments. As a result, an optimal additive and synergistic action was observed with piperaquine.